Indole derivatives as serotonin reuptake inhibitors

ABSTRACT

Compounds of the formula (I), the use thereof for the preparation of a medicament for the treatment of diseases associated with the serotonin receptor and/or serotonin reuptake, in particular for the preparation of a medicament as anxiolytic, antidepressant, neuroleptic and/or antihypertonic and/or for positively influencing obsessive-compulsive disorder (OCD), sleeping disorders, tardive dyskinesia, learning disorders, age-dependent memory disorders, eating disorders, such as bulimia or IBS, and/or sexual dysfunctions. The compounds bind to the 5-HT 1A  receptor

The present invention relates to novel indole derivatives, processes forthe preparation thereof and use of the compounds for the preparation ofmedicaments for the treatment and prophylaxis of diseases associatedwith serotonin reuptake and/or serotonin receptors (serotonin,5-hydroxytryptamine, 5-HT).

The following types of 5-HT receptor are known, for example: 5-HT_(1A),5-HT_(1B), 5-HT_(1D), 5-HT_(2A), 5-HT_(2B), 5-HT_(2C), 5-HT₃, 5-HT₄,5-HT₆, 5HT₇. Sub-types, such as, for example, 5-HT_(1Dα) and 5-HT_(1Dβ),which differ in tissue specificity, mode of action and furtherproperties, are also found.

WO9951575 discloses indole derivatives which influence 5-HT1Aauto-receptors and 5-HT transporters and can be employed for thetreatment of depression.

DE19514567 describes piperazinylbenzofurans having actions on thecentral nervous system, EP0655442 describes piperazine derivativeshaving a tachykinin-antagonistic action.

Indolepiperazine derivatives are known from EP0648767, U.S. Pat. No.5,532,241, EP0407844, EP0376607, BE771285, GB1075156, GB118064,FR1551082 and from EP 0 736 525. These compounds are effective serotoninreuptake inhibitors and 5-HT1A receptor agonists.

WO9616056, WO9617842, WO9718202, WO9718203, WO9745432 and WO9719943disclose indolepiperidine and indolepiperazine derivatives which areeffective 5-HT_(1Dα) receptor agonists. The compounds disclosed thereinare used for the treatment of diseases in connection with migraine owingto their vasoconstrictive action.

The invention had the object of finding novel compounds which can beused for the preparation of medicaments.

It has been found that the compounds of the formula I according to theinvention and physiologically acceptable acid-addition salts thereofhave valuable pharmacological properties while being well tolerated.Surprisingly, it has been found that the compounds of the formula 1according to the invention have actions on the central nervous system.They act as selective serotonin reuptake inhibitors, exhibitserotonin-agonistic and -antagonistic properties and thus influenceserotoninergic transmission. In particular, they exhibit5-HT_(1A)-agonistic actions and an affinity to serotoin receptorsub-type 5-HT₄.

The invention therefore relates to compounds of the formula I

X═N or CH,

R¹, R³=independently of one another H, OH, OA, CN, Hal, COR⁴ or CH₂R⁴,

R²═H, an optionally mono- or poly-Hal-substituted, linear or branchedalkyl having 1-6 C atoms, alkaryl, alkheteroaryl, or heteroaryl,

R⁴═OH, OA, NH₂, NHB or NB₂,

A, B=independently of one another alkyl having 1-6 C atoms,

m=2, 3, 4, 5 or 6 and

n=0, 1, 2, 3 or 4,

and physiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios.

Hal preferably denotes F, Cl or Br, but also I.

A and B are, independently of one another, preferably unbranched andhave 1, 2, 3, 4, 5, or 6 C atoms.

Alkyl having 1-6 C atoms preferably denotes methyl, ethyl, n-propyl,furthermore preferably isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl.

Alkaryl denotes alkyl having 1-6 C atoms connected to an aromatic ringsystem comprising 6 or 10 centres, such as, for example, benzyl orphenethyl.

Alkheteroaryl denotes alkyl having 1-6 C atoms connected to an aromaticheterocycle comprising 5, 6 or 10 centres, such as, for example,pyridin-2-ylmethyl.

Heteroaryl denotes a monovalent monocyclic or bicyclic heterocyclehaving 5-12 ring atoms, which has at least one aromatic ring, where 1, 2or 3 ring atoms are selected from N, O or S. Heteroaryl is optionallysubstituted, independently of one another, by 14 substituents, forexample selected from alkyl, cycloalkyl, cycloalkylalkyl, Hal, NO, CN,alkoxy, NH₂, acylamino, monoalkylamino, dialkylamino, haloalkyl,haloalkoxy or heteroalkyl. Examples of heteroaryls are pyridyl, furanyl,thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzofuranyl,tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolyl, tetrahydroquinolyl, isoquinolyl, benzimidazolyl,benzisoxazolyl, or benzothienyl, or derivatives thereof.

Preference is given to the compounds of the formula I in which

X═N,

R¹, R³=independently of one another CN, COR⁴ or CH₂R⁴,

R²=a linear or branched alkyl having 1-6 C atoms, alkaryl,alkheteroaryl, or heteroaryl,

R⁴═OH, NH₂, NHB or NB₂,

A, B=independently of one another alkyl having 1-6 C atoms,

m=4 and

n=0,

-   -   and physiologically acceptable salts, derivatives, solvates and        stereoisomers thereof, including mixtures thereof in all ratios.

Particular preference is given to the compounds

-   -   a.        5-{4-[4-(5-cyano-1-ethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide    -   b.        5-{4-[4-(5-cyano-1-isopropyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide    -   c.        5-{4-[4-(1-benzyl-5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide    -   d.        5-{4-[4-(5-cyano-1-propyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide    -   e.        5-{4-[4-(5-cyano-1-pyridin-2-ylmethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide        and    -   f.        5-{4-[4-(5-cyano-1-phenethyl-1H-indol-3-yl)butyl]piperazin-1-yl}-benzofuran-2-carboxamide        and in particular the compound        5-{4-[4-(5-cyano-1-methyl-1H-indol-3-yl)-butyl]piperazin-1-yl}benzofuran-2-carboxamide.

Also according to the invention are all physiologically acceptablesalts, derivatives, solvates and stereoisomers of these compounds,including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andhydrates and solvates of these compounds.

Pharmaceutically or physiologically acceptable derivatives are taken tomean, for example, salts of the compounds according to the invention andalso so-called prodrug compounds. Prodrug compounds are taken to meancompounds of the formula I modified by, for example, alkyl or acylgroups, sugars or oligopeptides which are rapidly cleaved or liberatedin the organism to give the active compounds according to the invention.These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115 (1995), 61-67.

Suitable acid-addition salts are inorganic or organic salts of allphysiologically or pharmacologically acceptable acids, for examplehalides, in particular hydrochlorides or hydrobromides, lactates,sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates,phosphates, methylsulfonates or p-toluenesulfonates.

Solvates of the compounds of the formula I are taken to mean adductionsof inert solvent molecules onto the compounds of the formula I whichform owing to their mutual attractive force. Solvates are, for example,hydrates, such as monohydrates or dihydrates, or alcoholates, i.e.addition compounds with alcohols, such as, for example, with methanol orethanol.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.Particular preference is given to mixtures of two stereoisomericcompounds.

The invention additionally relates to a process for the preparation ofthe compounds of the formula I, characterised in

-   -   a) that a compound of the formula II, in which R¹ and m have the        meanings indicated above and Y is a halogen, in particular        chlorine, or is an alcohol provided with a protecting group        known to the person skilled in the art,    -   is reacted with a compound II, in which R² has the meanings        indicated above and Z represents a leaving group known to the        person skilled in the art, such as, for example, p-tosyl,        trifluoromethanesulfonyl, methanesulfonyl, benzenesulfonyl, Br,        Cl or I    -   and    -   b) that the compound of the formula IV    -   obtained in accordance with a) is reacted with a compound of the        formula V or a salt thereof, in which R³, X and n have the        meanings indicated above,    -   in a solvent, optionally with addition of base, at the boiling        point of the solvent,    -   or    -   c) that the base of a compound of the formula I is converted        into one of its salts by treatment with an acid.

It is also possible to carry out the reaction in each case stepwise. Thestarting compounds of the formula II, III, VI and V are generally known.If they are novel, they can be prepared by methods known per se.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

The starting materials can be combined (melted) in the absence of asolvent in a sealed reaction vessel or an autoclave. However, it is alsopossible to allow the starting materials to react in the presence of aninert solvent.

Suitable inert solvents are, for example, heptane, hexane, petroleumether, benzene, toluene, xylene, trichloroethylene-,1,2-dichloroethanetetrachloromethane, chloroform or dichloromethane;alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanolor tert-butanol; ethers, such as diethyl ether, diisopropyl ether(preferred for substitution on the indole nitrogen), tetrahydrofuran(THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether (methyl glycol or ethyl glycol), ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) ordimethylformamide (DMF); nitriles, such as acetonitrile; esters, such asethyl acetate, carboxylic acids or acid anhydrides, such as, forexample, such as, acetic acid or acetic anhydride, nitro compounds, suchas nitromethane or nitrobenzene, if desired also mixtures of the saidsolvents with one another or mixtures with water.

The reaction can also be carried out in the heterogeneous phase,preferably using an aqueous phase and a benzene or toluene phase. Use ismade here of a phase-transfer catalyst, such as, for example,tetrabutylammonium iodide, and optionally an acylation catalyst, suchas, for example, dimethylaminopyridine.

The amount of solvent is not crucial, preferably 10 g to 500 g ofsolvent can be added per g of the compound of the formula I to bereacted.

It may be advantageous to add an acid-binding agent, for example analkali metal or alkaline earth metal hydroxide, carbonate or bicarbonateor other alkali metal or alkaline earth metal salts of weak acids,preferably a potassium, sodium or calcium salt, or to add an organicbase, such as, for example, triethylamine, dimethylamine, pyridine orquinoline, or an excess of the amine component.

Suitable reaction temperatures are at temperatures of 10 to 180° C.,preferably at 20 to 150° C. and very particularly preferably at 40 to100° C.

The reaction is preferably carried out at a pressure of 1 to 200 bar andat temperatures between −80° and +150° C., particularly preferably atroom temperature and atmospheric pressure. Preferably at 1.5 to 120 barand in particular at 2 to 100 bar.

The reaction is preferably carried out at a pH of 6 to 10.

The duration of the reaction depends on the selected reactionconditions. In general, the reaction duration is 0.5 hours to 10 days,preferably 1 to 24 hours. On use of a microwave, the reaction time canbe reduced to values of 1 to 60 minutes.

The compounds of the formula I and also the starting materials for thepreparation thereof are, in addition, prepared by known methods, asdescribed in the literature (for example in standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), thus, for example, underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se, which are notdescribed here in greater detail.

The compounds of the formula II can be obtained, after removal of thesolvent, by conventional work-up steps, such as, for example, additionof water to the reaction mixture and extraction. It may be advantageoussubsequently to carry out a distillation or crystallisation for furtherpurification of the product.

An acid of the formula I can be converted into the associated additionsalt using a base, for example by reaction of equivalent amounts of theacid and the base in an inert solvent, such as ethanol, followed byevaporation. Particularly suitable bases for this reaction are thosewhich give physiologically acceptable salts. Thus, the acid of theformula I can be converted into the corresponding metal salt, inparticular alkali metal or alkaline earth metal salt, or into thecorresponding ammonium salt using a base (for example sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate). Alsosuitable for this reaction are organic bases which give physiologicallyacceptable salts, such as, for example, ethanolamine.

On the other hand, a base of the formula I can be converted into theassociated acid-addition salt using an acid, for example by reaction ofequivalent amounts of the base and the acid in an inert solvent, such asethanol, followed by evaporation. Particularly suitable acids for thisreaction are those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, naphthalenemono- and disulfonic acids orlaurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

It has been found that the compounds of the formula I andphysiologically acceptable acid-addition salts thereof are welltolerated and have valuable pharmacological properties since theyexhibit particular actions on the central nervous system. In particular,they inhibit 5-HT reuptake. In addition, the compounds have highaffinity to the 5-HT_(x) receptors (in 5-HT_(x), X denotes: 1A or 4) andexhibit serotonin-agonistic and -antagonistic properties. Due to a5-HT-agonistic action and 5-HT reuptake inhibition, serotonin remains inthe synaptic cleft for longer and the serotonin action is reinforced.Active ingredients having such properties are therefore particularlysuitable as antidepressants and anxiolytics. The compounds of theformula I inhibit the binding of tritiated serotonin ligands tohippocampal receptors (Cossery et al., European J. Pharmacol. 140(1987), 143-155) and synaptosomal serotonin reuptake (Sherman et al.,Life Sci. 23 (1978), 1863-1870).

For in-vitro determination of 5-HT reuptake inhibition, synaptosomalreuptake inhibition (Wong et al., Neuropsycho-pharmacology 8 (1993),22-33) and p-chloroamphetamine antagonism (Fuller et al. J. Pharmacol.Exp. Ther. 212 (1980), 115-119) is measured. Serotonin reuptakeinhibition can in addition also be investigated with the aid of theWaldmeier method ex vivo in the brain tissue of mice (European J.Pharmacol. 1977, 46, 387-92), and by microdialysis, which is describedby DiChiara (Trends in Pharmacol. Sci., 11 (1990), 116-121). To thisend, a physiological solution is perfused through a microdialysiscontainer implanted into a rat brain. During this perfusion, thesolution takes up the neurotransmitters liberated in the brain and issubsequently analysed. Thus, the 5-HT content in the solution afterperfusion is proportional to the amount liberated in the brain and itincreases, for example, after administration of a 5-HT reuptakeinhibitor (Gardier et al., Fundam. Clin. Pharmacol., 10 (1996), 16-27).

The 5-HT_(1A)-agonistic action can be measured in vitro, for example,with the aid of the (serotonin) binding test, as described by Matzen etal. (J. Med. Chem., 43 (2000), 1149-57), in particular on page 1156 withreference to Eur. J. Pharmacol., 140 (1987), 143-155. In addition, the5-HT_(1A)-agonistic action can be measured with the aid of the GTPgammaStest described by Newman-Tancredi et al. (Eur. J. Pharmacol. 307 (1996),107-11).

Furthermore, changes in DOPA accumulation in the striatum and 5-HTaccumulation in the N. raphe may occur after administration of thecompounds of the formula I (Seyfried et al., Europ. J. Pharmacol. 160(1989), 31-41). In addition, analgesic and hypotensive actions mayoccur. Thus, in catheterised, conscious, spontaneously hypertonic rats(method cf. Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960),646-648), the directly measured blood pressure drops after peroraladministration of the compounds. Compounds of the formula I aretherefore also suitable for the prophylaxis and treatment of theconsequences of cerebral infarctions (apoplexia cerebri), such asstrokes and cerebral ischaemia.

The invention relates, in particular, to the use of the compounds of theformula I and physiologically acceptable salts, derivatives, solvatesand stereoisomers thereof, including mixtures thereof in all ratios, asserotonin receptor ligands and/or for serotonin reuptake inhibition. Inparticular, the use of the compounds of the formula I as 5-HT_(1A)agonists and as inhibitors of 5-HT reuptake is in accordance with theinvention.

The invention thus also relates, in particular, to the use of compoundsof the formula I and/or physiologically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, for the preparation of a medicament for the treatment ofdiseases, in particular of diseases associated with the serotoninreceptor and/or serotonin reuptake.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and can accordingly occur in variousenantiomeric forms. They can therefore be in racemic or in opticallyactive form.

Since the pharmaceutical efficacy of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In this cases, the end product or alternativelyeven the intermediates can be resolved to give enantiomeric compounds,by chemical or physical measures known to the person skilled in the art,or even employed as such in the synthesis.

Since compounds of the formula I inhibit serotonin reuptake and at thesame time have 5-HT_(1A)-agonistic properties, they are particularlysuitable as antidepressants and anxiolytics.

The invention therefore also relates to the use of compounds of theformula I and/or physiologically acceptable salts, derivatives,solvates, and stereoisomers thereof, including mixtures thereof in allratios, for the preparation of a medicament as anxiolytic,antidepressant, neuroleptic and/or antihypertonic and/or for positivelyinfluencing obsessive-compulsive disorder (OCD), sleeping disorders,tardive dyskinesia, learning disorders, age-dependent memory disorders,eating disorders, such as bulimia or IBS, and/or sexual dysfunctions.The use for the preparation of a medicament as antidepressant isparticularly preferred. Compounds of the formula I may furthermore andalso be used as intermediates for the preparation of other medicamentactive ingredients.

The compounds of the formula I are suitable both in veterinary and alsoin human medicine for the treatment of dysfunctions of the centralnervous system and of inflammation.

The invention thus relates to the use of compounds of the formula Iand/or physiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of psychoses,schizophrenia, schizo-affective psychosis, cyclothymia, epilepsy,cramps, depression (sub-types of severe depression and cyclothymicdepression), pathogenic anxiety states (sub-types of panic attacks withor without agoraphobia), superexcitation, hyper-activity, stressillnesses, post-traumatic stress disorders, sleeping disorders,narcolepsy, cyclic manic depression, attention disorders in children andyouths, severe developmental disorders and disorders of social behaviourwith mental retardation, obsessive-compulsive disorders in the narrower(OCD) and broader sense (OCSD), addiction disorders, disorders innutrient uptake or eating disorders, for example bulimia, obesity oranorexia nervosa, in particular irritable bowel syndrome (IBS),fibromyalgia, and psychiatric symptoms in senile dementia andAlzheimer's-type dementia, cognitive impairments (learning and memorydisorders), in particular age-dependent memory disorders, dementia,tardive dyskinesia, neurodegenerative diseases, such as Parkinson'sdisease, Alzheimer's disease, Huntington's disease, lathyrism,amyotrophic lateral sclerosis, Lewy bodies dementia, Tourette'ssyndrome, sexual dysfunctions, premenstrual syndrome, acromegaly,hypogonadism, secondary amenorrhoea, undesired puerperal lactation,extrapyramidal motor disorders, for the treatment of side effectsarising in the treatment of extrapyramidal motor disorders withconventional anti-Parkinson's medicaments and of extrapyramidal symptoms(EPS), tension states, side effects of hypertonia treatment induced byneuroleptics (for example with a-methyldopa) or for the prophylaxis,treatment and control of cerebral infarctions (apoplexia cerebri), suchas strokes and cerebral ischaemia, or for the treatment of pain, inparticular chronic pain, migraine, CNS trauma, hypoglycaemia, asthma,glaucoma, cytomegaly and for the treatment of other degenerative retinaldiseases, incontinence, tinnitus, or for the treatment of loss ofhearing induced by aminoglycoside antibiotics.

In particular, however, they are suitable as medicament activeingredients for anxiolytics, antidepressants, antipsychotics,neuroleptics, antihypertonics and/or for positively influencingobsessive-compulsive disorder (OCD), sleeping disorders, tardivedyskinesia, learning disorders, age-dependent memory disorders, eatingdisorders, such as bulimia or IBS, and/or sexual dysfunctions.

The compounds of the formula I can be used for the preparation ofpharmaceutical compositions, in particular by non-chemical methods.Here, they are brought into a suitable dosage form together with atleast one solid, liquid and/or semi-liquid excipient or adjuvant andoptionally in combination with one or more further active ingredient(s).

The invention therefore furthermore relates to pharmaceuticalcompositions comprising at least one compound of the formula I and/orphysiologically acceptable salts, derivatives, solvates, andstereoisomers thereof, including mixtures thereof in all ratios. Theinvention also relates, in particular, to pharmaceutical compositionswhich comprise further excipients and/or adjuvants and also topharmaceutical compositions which comprise at least one furthermedicament active ingredient.

The invention also relates, in particular, to a process for thepreparation of a pharmaceutical composition, characterised in that acompound of the formula I and/or one of its physiologically acceptablesalts, derivatives, solvates, and stereoisomers, including mixturesthereof in all ratios, is brought into a suitable dosage form togetherwith a solid, liquid or semi-liquid excipient or adjuvant and optionallywith a further medicament active ingredient.

The pharmaceutical compositions according to the invention can be usedas medicaments in human or veterinary medicine.

Suitable excipient substances are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils (such as sunflower oil or cod-liver oil), benzylalcohols, polyethylene glycols, gelatine, carbohydrates, such as lactoseor starch, magnesium stearate, talc, lanolin or Vaseline. On the basisof his expert knowledge, the person skilled in the art is familiar withwhich adjuvants are suitable for the desired medicament formulation.Besides solvents, for example water, physiological saline solution oralcohols, such as, for example, ethanol, propanol or glycerol, sugarsolutions, such as glucose or mannitol solutions, or a mixture of thesaid solvents, gel formers, tablet assistants and otheractive-ingredient excipients, it is possible to use, for example,lubricants, stabilisers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, antioxidants, dispersants, antifoams,buffer substances, flavours and/or aroma substances or flavourcorrectants, preservatives, solubilisers or dyes. If desired,compositions or medicaments according to the invention may comprise oneor more further active ingredients, for example one or more vitamins.

The invention also relates to a set (kit) consisting of separate packsof

-   -   a) an effective amount of a compound of the formula I and/or        physiologically acceptable salts, derivatives, solvates and        stereoisomers thereof, including mixtures thereof in all ratios,        and    -   b) an effective amount of a further medicament active        ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may comprise, for example, separateampoules in each of which an effective amount of a compound of theformula I and/or pharmaceutical acceptable derivatives, solvates,stereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient is present indissolved or lyophilised form.

Suitable for enteral administration (oral or rectal) are, in particular,tablets, dragees, capsules, syrups, juices, drops or suppositories,suitable for parenteral administration (subcutaneous or intravenous) aresolutions, preferably oily or aqueous solutions, furthermoresuspensions, emulsions or implants, suitable for topical application areointments, creams, pastes, lotions, gels, sprays, foams, aerosols,solutions (for example solutions in alcohols, such as ethanol orisopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol ormixtures thereof with one another and/or with water) or powders.Liposomal compositions also come into consideration, in particular fortopical applications.

The compounds and/or physiologically acceptable salts and solvatesthere-of may also be lyophilised and the resultant lyophilisates used,for example, for the preparation of injection preparations. They canfurthermore be administered as nasal sprays.

The compounds according to the invention can be administered to humansor animals, in particular mammals, such as apes, dogs, cats, rats ormice, and used in the therapeutic treatment of the human or animal bodyand in combating the above-mentioned diseases. They can furthermore beused as diagnostic agents or as reagents.

On use of compositions or medicaments according to the invention, thecompounds according to the invention and/or physiologically acceptablesalts and solvates thereof are generally used analogously to known,commercially available compositions or preparations, preferably in dosesbetween 0.1 and 500 mg, in particular 5 and 300 mg, per administrationunit. The daily dose is preferably between 0.001 and 250 mg/kg, inparticular 0.01 and 100 mg/kg, of body weight. The composition may beadministered one or more times per day, for example twice, three timesor four times per day. However, the individual dose for a patientdepends on a large number of individual factors, such as, for example,on the efficacy of the compound used in each case, on the age, bodyweight, general state of health, sex, diet, on the time and method ofadministration, on the excretion rate, on the combination with othermedicaments and on the severity and duration of the particular disease.Oral administration is preferred.

A measure of the uptake of a medicament active ingredient in an organismis its bioavailability. If the medicament active ingredient is suppliedintravenously to the organism in the form of an injection solution, itsabsolute bioavailability, i.e. the fraction of the drug which reachesthe systemic blood, i.e. the general circulation, in unchanged form, is100%. In the case of oral administration of a therapeutic activeingredient, the active ingredient is generally in the form of a solid inthe formulation and must therefore first be dissolved so that it is ableto overcome the entry barriers, for example the gastrointestinal tract,the oral mucous membrane, nasal membranes or the skin, in particular thestratum corneum, or can be absorbed by the body. Pharmacokinetic data,i.e. on the bioavailability, can be obtained analogously to the methodof J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318.

Even without further embodiments, it is assumed that a person skilled inthe art will be able to utilise the above description in the broadestscope. The preferred embodiments should therefore merely be regarded asdescriptive disclosure, but absolutely not as a disclosure which islimiting in any way. The following examples are thus intended to explainthe invention without limiting it. Unless stated otherwise, percentagesdenote per cent by weight. All temperatures are indicated in degreesCelsius. “Conventional work-up”: water is added if necessary, pH valuesof between 2 and 10 are set if necessary, depending on the constitutionof the end product, the mixture is extracted with ethyl acetate ordichloromethane, the phases are separated, the organic phase is driedover sodium sulfate, filtered and evaporated, and the residue ispurified by chromatography on silica gel and/or by crystallisation.

Rf values on silica gel;

Mass spectrometry: EI (electron impact ionisation): M⁺

-   -   FAB (fast atom bombardment): (M+H)⁺

THF (tetrahydrofuran), NMP (N-methylpyrrolidone), DMSO (dimethylsulfoxide), EA (ethyl acetate), MeOH (methanol), TLC (thin-layerchromatography)

The following substances have been synthesised and characterised.However, the substances can also be prepared and characterised by theperson skilled in the art by other methods.

EXAMPLE 1

Synthesis of5-{4-[4-(5-cyano-1-methyl-1H-indol-3-yl)butyl]piperazin-1-yl}-benzofuran-2-carboxamide

a.: 0.8 g (20 mmol) of NaH are suspended in 20 ml of THF, and a solutionof 4.6 g (20 mmol) of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in 50ml of THF is added dropwise at room temperature. The yellow solution isstirred for a further 30 minutes, and a solution of 1.2 ml (20 mmol) ofiodomethane in 30 ml of THF is then added dropwise. The yellow solutionis stirred at room temperature for 1 h. The reaction solution issubsequently evaporated, and the residue is extracted by shaking withethyl acetate and water. The organic phase is washed with water, driedusing sodium sulfate and evaporated, giving 5.4 g of oily residue, whichis crystallised using 15 ml of diethyl ether and 5 ml of petroleumether, filtered off with suction and washed with a little diethyl ether.Drying in air gives 3.2 g of coarse pale-yellow crystals [M+H⁺] ESI-MS457.

b.: 540 mg (2.2 mmol) of the indole obtained in accordance with a. aresuspended in 5 ml of NMP together with 490 mg (2 mmol) of5-piperazin-1-yl-benzofuran-2-carboxamide and 0.9 ml of triethylamineand heated. The resultant solution is stirred twice for 4 hours at abath temperature of 120° C. and cooled to room temperature over thecourse of 10 hours. The reaction mixture is stirred into 100 ml ofwater. During this, fine crystals deposit. These are filtered off withsuction, washed with water and dried overnight in air. The resultant 0.9g of pale-brown crystals are finally purified by chromatography to give0.8 g of pale crystals.

These are dissolved in hot acetone, and one millilitre of ethanolic HClis added. White crystals immediately deposit. These are again stirredhot, filtered off with suction and washed with acetone.

Calculated C=61.4 H=5.9 N=13.2 Cl=13.4

Found C=60.7 H=6.0 N=13.1 Cl=12.7

Calculated on the basis of dihydrochloride

EXAMPLE 2

The following products, inter alia, are prepared analogously to Example1: [M + H]⁺ No. Structure (ESI-MS) 1

471 5-{4-[4-(5-Cyano-1-ethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide 2

485 5-{4-[4-(5-Cyano-1-isopropyl-1H-indol-3-yl)butyl]piperazin-1-yl}-benzofuran-2-carboxamide 3

533 5-{4-[4-(1-Benzyl-5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide 4

485 5-{4-[4-(5-Cyano-1-propyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide 5

534 5-{4-[4-(5-Cyano-1-pyridin-2-ylmethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide 6

5475-{4-[4-(5-Cyano-1-phenethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzo-furan-2-carboxamide

EXAMPLE 3 Results of the Receptor Binding Tests

Many of the compounds synthesised have nanomolar affinity to the5-HT_(1A) receptors and nanomolar reuptake inhibition of serotonin.

5-{4-[4-(5-Cyano-1-methyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide(see Example 1)

-   -   SSRI 2.6 nmol/I (IC50)    -   5HT_(1A) 96 nmol/l (IC50)    -   5HT₄ 21 nmol/I (IC50)

EXAMPLE 4 Injection Vials

A solution of 100 g of a compound of the formula I and 5 g of disodiumhydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5using 2N hydrochloric acid, sterile filtered, transferred into injectionvials, lyophilised under sterile conditions and sealed under sterileconditions. Each injection vial contains 5 mg of a compound of theformula I.

EXAMPLE 5 Suppositories

A mixture of 20 g of a compound of the formula I is melted with 100 g ofsoya lecithin and 1400 g of cocoa butter, poured into moulds and allowedto cool. Each suppository contains 20 mg of a compound of the formula I.

EXAMPLE 6 Solution

A solution is prepared from 1 g of a compound of the formula I, 9.38 gof NaH₂PO₄ 2 H₂O, 28.48 g of Na₂HPO₄ 12 H₂O and 0.1 g of benzalkoniumchloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, andthe solution is made up to 1 l and sterilised by irradiation. Thissolution can be used in the form of eye drops.

EXAMPLE 7 Ointment

500 mg of a compound of the formula I are mixed with 99.5 g of Vaselineunder aseptic conditions.

EXAMPLE 8 Tablets

A mixture of 1 kg of a compound of the formula I, 4 kg of lactose, 1.2kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate ispressed in a conventional manner to give tablets in such a way that eachtablet contains 10 mg of a compound of the formula I.

EXAMPLE 9 Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE 10 Capsules

2 kg of a compound of the formula I are introduced in a conventionalmanner into hard gelatine capsules in such a way that each capsulecontains 20 mg of a compound of the formula I.

EXAMPLE 11 Ampoules

A solution of 1 kg of a compound of the formula I in 60 l of bidistilledwater is sterile filtered, transferred into ampoules, lyophilised understerile conditions and sealed under sterile conditions. Each ampoulecontains 10 mg of a compound of the formula I.

1. Compounds of the formula I

X═N or CH, R¹, R³=independently of one another H, OH, OA, CN, Hal, COR⁴or CH₂R⁴, R²═H, an optionally mono- or poly-Hal-substituted, linear orbranched alkyl having 1-6 C atoms, alkaryl, alkheteroaryl, orheteroaryl, R⁴═OH, OA, NH₂, NHB or NB₂, A, B=independently of oneanother alkyl having 1-6 C atoms, m=2, 3, 4, 5 or 6 and n=0, 1, 2, 3 or4, and physiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 2.Compounds according to claim 1 in which X═N, R¹, R³=independently of oneanother CN, COR⁴ or CH₂R⁴, R²=a linear or branched alkyl having 1-6 Catoms, alkaryl, alkheteroaryl, or heteroaryl, R⁴═OH, NH₂, NHB or NB₂, A,B=independently of one another alkyl having 1-6 C atoms, m=4 and n=0,and physiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 3.Compounds according to claim 1 a.5-{4-[4-(5-cyano-1-methyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide b.5-{4-[4-(5-cyano-1-ethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide c.5-{4-[4-(5-cyano-1-isopropyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamided.5-{4-[4-(1-benzyl-5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamidee.5-{4-[4-(5-cyano-1-propyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamidef.5-{4-[4-(5-cyano-1-pyridin-2-ylmethyl-1H-indol-3-yl)butyl]piperazin-1-yl}-benzofuran-2-carboxamideg.5-{4-[4-(5-cyano-1-phenethyl-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide4. Process for the preparation of the compounds of the formula I,characterised in that a) a compound of the formula II, in which R¹ and mhave the meanings indicated in claim 1 and Y is a halogen or is analcohol provided with a protecting group known to the person skilled inthe art,

is reacted with a compound of the formula III, in which R² has themeanings indicated in claim 1 and Z represents a leaving group known tothe person skilled in the art, such as, for example, p-tosyl,trifluoromethanesulfonyl, methanesulfonyl, benzenesulfonyl, Br, Cl or I

and b) in that the compound of the formula IV

obtained in accordance with a) is reacted with a compound of the formulaV or a salt thereof, in which R³, X and n have the meanings indicated inclaim 1,

in a solvent, optionally with addition of base, at the boiling point ofthe solvent, or c) in that the base of a compound of the formula I isconverted into one of its salts by treatment with an acid.
 5. Compoundsaccording to claim 1 and physiologically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, as serotonin receptor ligands and/or for serotonin reuptakeinhibition.
 6. Pharmaceutical composition comprising at least onecompound according to claim 1 and/or physiologically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 7. Pharmaceutical composition, according to claim6 comprising further excipients and/or adjuvants.
 8. Pharmaceuticalcomposition comprising at least one compound according to claim 1 and/orphysiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and atleast one further medicament active ingredient.
 9. Process for thepreparation of a pharmaceutical composition, characterised in that acompound according to claim 1 and/or one of its physiologicallyacceptable salts, derivatives, solvates and stereoisomers, includingmixtures thereof in all ratios, is brought into a suitable dosage formtogether with a solid, liquid or semi-liquid excipient or adjuvant. 10.Use of compounds according to claim 1 and/or physiologically acceptablesalts, derivatives, solvates and stereoisomers thereof, includingmixtures thereof in all ratios, for the preparation of a medicament forthe treatment of diseases.
 11. Use of compounds according to claim 1and/or physiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of diseases associatedwith the serotonin receptor and/or serotonin reuptake.
 12. Use ofcompounds according to claim 1 and/or physiologically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, for the preparation of a medicament asanxiolytic, antidepressant, neuroleptic and/or antihypertonic and/or forpositively influencing obsessive-compulsive disorder (OCD), sleepingdisorders, tardive dyskinesia, learning disorders, age-dependent memorydisorders, eating disorders, such as bulimia or IBS, and/or sexualdysfunctions.
 13. Use of compounds according to claim 1 and/orphysiologically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of psychoses,schizophrenia, schizo-affective psychosis, cyclothymia, epilepsy,cramps, depression (subtypes of severe depression and cyclothymicdepression), pathogenic anxiety states (sub-types of panic attacks withor without agoraphobia), superexcitation, hyperactivity, stressillnesses, post-traumatic stress disorders, sleeping disorders,narcolepsy, cyclic manic depression, attention disorders in children andyouths, severe developmental disorders and disorders of social behaviourwith mental retardation, obsessive-compulsive disorders in the narrower(OCD) and broader sense (OCSD), addiction disorders, disorders innutrient uptake or eating disorders, for example bulimia, obesity oranorexia nervosa, in particular irritable bowel syndrome (IBS),fibromyalgia, and psychiatric symptoms in senile dementia andAlzheimer's-type dementia, cognitive impairments (learning and memorydisorders), in particular age-dependent memory disorders, dementia,tardive dyskinesia, neurodegenerative diseases, such as Parkinson'sdisease, Alzheimer's disease, Huntington's disease, lathyrism,amyotrophic lateral sclerosis, Lewy bodies dementia, Tourette'ssyndrome, sexual dysfunctions, premenstrual syndrome, acromegaly,hypogonadism, secondary amenorrhoea, undesired puerperal lactation,extrapyramidal motor disorders, for the treatment of side effectsarising in the treatment of extrapyramidal motor disorders withconventional anti-Parkinson's medicaments and of extrapyramidal symptoms(EPS), tension states, side effects of hypertonia treatment induced byneuroleptics (for example with α-methyldopa) or for the prophylaxis,treatment and control of cerebral infarctions (apoplexia cerebri), suchas strokes and cerebral ischaemia, or for the treatment of pain, inparticular chronic pain, migraine, CNS trauma, hypoglycaemia, asthma,glaucoma, cytomegaly and for the treatment of other degenerative retinaldiseases, incontinence, tinnitus, or for the treatment of loss ofhearing induced by aminoglycoside antibiotics.
 14. Set (kit) consistingof separate packs of a) an effective amount of a compound according toclaim 1 and/or physiologically acceptable salts, derivatives, solvatesand stereoisomers thereof, including mixtures thereof in all ratios, andb) an effective amount of a further medicament active ingredient.